Iron is a required nutrient but can be toxic in high concentrations. Iron deprivation, as manifested by anemia, may be the most common nutrient deficiency in the world. Iron deprivation also leads to severe defects in developing embryos. In humans iron limitation results in low birth weight and developmental defects that may not be reversible. In contrast, iron overload leads to disease. The toxicity of iron is ascribed to its ability to participate in Fenton reactions generating oxygen radicals that damage biological macromolecules. We have determined that iron supplementation or deprivation can affect cellular physiology by changing transcriptional patterns. Alteration of transcriptional patterns results from an effect of iron on transcriptional activators and repressors, independent of the well-studied iron regulatory protein system. Some of these effects are direct but others are indirect, as they require protein synthesis. The mechanism by which iron affects transcription is the focus of this application. The goal of this grant proposal is to determine how iron leads to transcriptional activation and repression and determined the mechanism and consequences of the peptide hormone hepcidin as a transcriptional regulator of genes required for iron acquisition and distribution. PUBLIC HEALTH RELEVANCE: This study provides new information on how iron distribution is regulated and how changes in iron distribution affect metabolism and developmental programs. The results will lead to better treatment of disorders related to either iron deficiency or iron excess.